Bad bargain

All of us want cheaper medicine—but not if it costs us our health. Troubling reactions and a series of recalls are making some doctors wonder, Are generic drugs as safe as the FDA says they are? SELF investigates.

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Just when Beth Hubbard should have been feeling great, her healthfell apart.

A 34-year-old housewares designer in the St. Louis area, Hubbard hadrecently gotten married. She liked the creativity of her career. Andshe’d conquered her mild depression and fatigue with a combination ofexercise, rest and medicine, including the antidepressant Wellbutrin XL.But in the fall of 2006, shortly after she refilled herprescription—her pharmacy giving her this time Budeprion XL, ageneric version of the drug—her good health gave way.

Within a month, she had gained 15 pounds, couldn’t sleep well,developed gastrointestinal problems and felt such extreme fatigue andlack of motivation that she thought about quitting her job. She criedand called in sick for days at a time. “I chalked it up to exhaustionafter the whirlwind of the wedding and honeymoon,” Hubbard says.

Yet she wasn’t getting better. Her doctor referred her to fourspecialists, but none, she complains, “were really listening tome—they were just anxious to give me another drug.” They diagnosedher alternately with severe allergies, a heart murmur, a slow thyroid,irritable bowel syndrome, gluten intolerance, mononucleosis and chronicpain. She cycled on and off different drugs: Ambien to help her sleep atnight; Provigil to keep her awake during the day; Allegra, Zyrtec andNasacort for allergies; Lexapro, Zoloft and Xanax for anxiety anddepression; Zelnorm for bowel problems. And she continued on theBudeprion XL the entire time. “I was fighting for almost a year with theinsurance company over all the tests and therapy I needed,” Hubbardadds.

After eight months of struggling with her mystery ailments, she wasout to dinner with a friend and mentioned that she needed to refill herprescription. Her friend said she’d recently gone off Wellbutrin and hadsome leftover pills Hubbard could use.

Within a week, Hubbard’s troubling symptoms vanished. Her energycame roaring back. And that is when she finally connected the dots: Herproblems had begun mere days after she first took the generic. Becausegenerics had always worked well for other conditions, she says, “I nevereven gave it a second thought or mentioned the pharmacy’s switch to mydoctor.” Until now.

She called her doctor to complain about the generic and request anew prescription for the brand name only. The nurse’s response flooredher. “Yes,” the nurse said matter-of-factly. “We hear that all thetime.”

Why your M.D. is worried

If you took a prescription pill recently, odds are it was generic:Nowadays, generics constitute almost 70 percent of all the prescriptionsdispensed nationwide, racking up $58 billion in sales in 2007. Anxiousto cut costs, health insurers are stampeding to switch patients to drugsthat are cheaper to make, test and ultimately buy because theirmanufacturers can piggyback on the research and marketing already doneby brand-name-drug companies. Pharmacists in most states are also freeto give patients whichever version of a drug is cheapest for them tosupply, without telling the prescribing doctor; in some states,pharmacies are required to make this switch. And few of us complain whenit happens: Women who wouldn’t dream of substituting Diet Pepsi for DietCoke, simply because of the taste, eagerly swap vital medications,because the change can cut co-pays in half.

Many lawmakers and health-policy experts say the trend has littledownside. “Generic drugs have the same active ingredient that brand-namedrugs do and are made in FDA-approved plants, just as brand-name drugsare,” says Aaron S. Kesselheim, M.D., an instructor in medicine atHarvard Medical School in Boston. In an analysis recently published inThe Journal of the American Medical Association, Dr. Kesselheim revieweddata from 47 clinical studies and found no evidence that patients onbrand-name cardiovascular drugs had clinical outcomes superior to thoseon generics. Given these results, and the lengths that somebrand-name-drug companies have gone to protect their patents andprofits, it’s easy to believe that any supposed problems with genericsare “a story cooked up by Big Pharma”—the conclusion reached byconsumer watchdog Peter Lurie, M.D., deputy director of thehealth-research group at Public Citizen in Washington, D.C.

But a yearlong investigation by SELF—including more than 50interviews and records leaked from one of the world’s largestgeneric-drug companies, Ranbaxy Laboratories—raises questionsabout whether some new generics are as safe or effective as the brandnames. Although Dr. Kesselheim’s review looked at all of the availabledata, many of those studies were completed before the recent flood ofgenerics hit the market and many generic-drug factories moved overseas.In FDA applications for new generic drugs, nearly 90 percent of thefactories providing active ingredients are located overseas, where theagency’s inspection rate dropped 57 percent between 2001 and 2008.

“The average citizen would want to know that someone is checkingthat manufacturers are making the drugs they got approval to make,” saysWilliam K. Hubbard of Chapel Hill, North Carolina, associatecommissioner for policy and planning for the FDA from 1991 to 2005 (andno relation to Beth). “That’s not happening, and the risk to consumersis potentially huge. I take generic drugs when they’re prescribed forme, but my confidence in them is lower than it was a year ago—andgoing down.”

Generics, which came into widespread use after Congress streamlinedtesting requirements in 1984, are supposed to be tightly regulated. Inthe late 1980s, after companies were caught paying off inspectors inorder to get generic drugs approved, the FDA overhauled its rules. Theagency vowed to inspect each factory before giving the green light toany application. And it newly required any generic-drug maker seekingapproval to make one test lot of the proposed drug and then to producethree larger lots to show its manufacturing capabilities. “I have toldthe industry they are in charge of the health of the American public,”says Gary Buehler, director of the FDA’s Office of Generic Drugs,adding, “We have come a long way in how we do inspections.”

But SELF found that the FDA’s reforms have largely fallen by thewayside. Few applications trigger inspections, according to sourcesknowledgeable about the process, and instead of the three required lots,companies are making one or none. Manufacturing problems have come tolight, with six generic companies recalling 20 products in 2008. KVPharmaceutical Company, a maker of heart and pain medicine, recalledeverything it made. “The FDA is satisfied that generics are OK,” saysNada Stotland, M.D., a psychiatrist in Chicago and the president of theAmerican Psychiatric Association. “My question is, Are we satisfied?”

Are generics really the same?

Between 2000 and 2008, the number of new generic drugs put forth forFDA approval went up 40 percent and approvals doubled, with roughly 600cleared to be sold last year. “Generic companies are popular on CapitolHill because the industry is powerful and voters are anxious for cheaperdrugs. There was always pressure on us to reduce barriers to entry,”says Scott Gottlieb, M.D., deputy commissioner for medical andscientific affairs for the FDA from 2005 to 2007. (Dr. Gottlieb is now aresident fellow at the American Enterprise Institute, a conservativethink tank in Washington, D.C., and also advises brand-name-drugcompanies.)

Because brand-name medications have already been clinically tested,generic companies applying for FDA approval don’t have to repeat thatprocess on their versions. Instead, they must test their medicine on aminimum of 20 people; subjects take a single dose, so the drug is nottested over time. If tests show the generic contains the same activeingredient that the original does and delivers about the same dose, thenthe FDA considers it “bio­equivalent” and clears it to be sold.

But as Beth Hubbard discovered, patients are finding starkdifferences among drugs the FDA has deemed equivalent. PharmacologistJoe Graedon and his wife, Terry, cohosts of the public radio show ThePeople’s Pharmacy, have fielded complaints about dozens of generics fordepression, hypertension, high cholesterol and more. Consumers describeddrugs that had no effect, caused bizarre side effects or made conditionsworse. Joe Graedon says he has been “astounded” by the outpouring. “I’mnot in the back pocket of the pharmaceutical companies—I wantgenerics to be good,” he says. “But the more we dug, the more werealized nobody is monitoring the equivalence of these drugs.”

After her ordeal, Hubbard hit the Internet. Amazed, she scrolledthrough hundreds of comments at PeoplesPharmacy.org, many from patientswho had switched to the same drug she had—Budeprion XL 300milligrams, which Impax Laboratories makes and Teva PharmaceuticalIndustries distributes. One patient wrote, “I have no history ofsuicidality, but a day after switching to the generic, I went into aweek of steadily rising panic…. I was psychotic, self-loathingway WAY beyond anything I have ever experienced. I made it through theworst of it, called a suicide hotline, took two Ativan and didn’t takeany more of the Budeprion. The next day I felt much better, and todayI’m back to my normal self.”

If the drugs were truly bioequivalent, what could account for suchdivergent reactions? Last fall, the Graedons collaborated withConsumerLab.com, an independent testing laboratory in White Plains, NewYork, to find out. Testing revealed that the 300 mg Budeprion XL doseHubbard had taken dumped four times as much active ingredient during thefirst two hours as the brand name did. Graedon compares the effect toguzzling alcohol. “If you sip a glass of wine over the course of two orthree hours, you’re not going to feel drunk,” he explains. “But if youdrink the whole thing in 15 minutes, you’re getting too much too fast.”

Release formulas, which control how quickly a drug dissolves in yourbloodstream, are something drug companies carefully develop and patent.And these release-formula patents often remain in place after the patenton a drug’s active ingredient has expired. That means generic companiesmust sometimes engineer their own release mechanism, as happened in thecase of Budeprion XL. After complaints started rolling in, the FDAconcluded in a 2008 report that patients’ problems were more likelycaused by normal relapses of depression than by differences in thedrugs, and Teva stressed that it followed all the FDA’s rules. But thatreport—and the original approval of the 300 mg pill—wasbased solely on data Teva had submitted for the 150 mg pill; theagency’s judgment was that the doses were proportional and would behavesimilarly in the body. “Neither the FDA nor Teva did the requiredbioequivalence studies for this pill,” counters Tod Cooperman, M.D.,president of ConsumerLab.com.

Buehler notes that the FDA won’t approve generics that itsscientists deem to have “clinically significant” differences in releaserates compared to the original. But the bioequivalence studies they basethis judgment on aren’t public, so doctors and patients have no way ofknowing when the FDA has found a difference and how dramatic it is. Norcan they easily find out about differences in fillers and additives,which might change the release rate or in rare cases trigger allergicreactions. “It’s scary to think the FDA would approve something it knowsis different and still call it equivalent,” Dr. Cooperman says.

Some physicians are concerned not only with how fast genericsdeliver their dose but also about the strength of the dose itself.Because for some drugs, such as those that treat epilepsy and heartdisease, even small differences in potency can mean the differencebetween an ineffective underdose and a toxic overdose.

Stephanie Bornice, a 22-year-old stay-at-home mother of two inBristol, Pennsylvania, and an epilepsy sufferer since 2002, says shehadn’t had a seizure in six years, thanks to the medication Trileptal.But last year, after about a month on the generic, oxcarbazepine,Bornice began to have frightening and familiar symptoms, like tremorsbefore an earthquake. “Someone would be talking, and I wouldn’tunderstand him, or my sight would blur,” she remembers. One afternoon, aseizure came on suddenly. She rushed to put her newborn son safely inhis crib before, she says, “everything turned black.”

Bornice’s doctor at the time, Jacqueline French, M.D., professor ofneurology at New York University Comprehensive Epilepsy Center in NewYork City, quickly confirmed Bornice’s suspicions that the generic wascausing the problem and switched her back. Dr. French describes the caseas a “clear-cut failure” of the generic—and not the only one shehas seen. “The FDA is telling us that the drugs [dosages] are the samewithin a certain margin and that should be OK,” Dr. French says. “Butthere are patients holding off seizures by the skin of their teeth.”

Ensuring the correct dose becomes even trickier when pharmacistsswitch customers from one generic version of a drug to another, saysJohn S. Antalis, M.D., a family physician in Dalton, Georgia, who hasserved on the safe-medication-use committee of U.S. Pharmacopeia, anonprofit organization in Rockville, Maryland, that sets officialstandards for all medications. Dr. Antalis cites the dozens of versionsof warfarin, the generic for the blood thinner Coumadin. It’s a drugthat requires patients to have regular blood tests; they risk bloodclots if they have too small a dose and internal bleeding if they gettoo much. It became much harder to monitor the clotting in patients’blood, Dr. Antalis says, because they were being shifted between so manyversions of warfarin that it was hard to say which drug was having whateffect. “I try to stay on top of any subtle hint of change, but it’sdifficult,” he says.

Physicians’ groups, including the American Academy of Neurology inSt. Paul, Minnesota; the American Heart Association in Dallas; and theEndocrine Society in Chevy Chase, Maryland—all of whose membersprescribe drugs that require delicate dosing—have warned doctorsto look out for reactions to generics. They’ve also called on the FDA tostudy the issue in more detail. (Many medical societies have ties tobrand-name companies; for instance, Abbott Laboratories, maker of thepopular brand-name thyroid drug Synthroid, has donated to the AmericanAssociation of Clinical Endocrinologists in Jacksonville, Florida.)

Some experts chalk up complaints to the fulfillment of expectations:We believe a generic will be worse, so it is. “People hear the wordgeneric, and they think about generic cornflakes or plastic wrap,” Dr.Kesselheim says. Others dispute that notion. “Patients look forward tohaving a lower co-pay,” says Adam Keller Ashton, M.D., clinicalprofessor of psychiatry at the State University of New York at BuffaloSchool of Medicine and Biomedical Sciences. (Dr. Ashton says he hasearned money from the makers of Wellbutrin in the past but not for theprevious two years, and he has no ties to generics.) He estimates thatat least 75 of his patients have complained about the 300 mg genericversion of Wellbutrin XL. “If it was in their head, why wasn’t it intheir head when other brands went generic?” he says, adding that many ofhis patients felt so bad that if he hadn’t intervened, “it might haveprogressed to the point to where lives were in jeopardy.”

Dangerous factories

Stephanie T., a 33-year-old in New York City, never gave muchthought to where her prescription drugs were manufactured. She knew onlythat they were helping her get healthy after years of battlingschizoaffective disorder. In January 2007, she was productive again,back in school and studying for a degree in medical coding and billing.She had been taking a version of fluoxetine (the generic of Prozac) by aCroatian company, Pliva; then her pharmacy switched her to a fluoxetinemade by the Indian generic giant Ranbaxy. Over the next six months, shefell into a deep depression. “I was lying on the couch all day long,”recalls Stephanie, who asked SELF not to publish her last name. “Iwasn’t eating; I couldn’t get my schoolwork done. I was crying all thetime.” If it weren’t for her family, she says, “I don’t think I’d bearound.”

Out of the blue, Stephanie’s pharmacy switched her back to themedicine made by Pliva. “Within days, I was a brand-new person. Iremember lying in bed thinking, What did I do differently?” she says.”When people are mentally ill, changing their drugs is like playing withsomeone’s mind. I could have committed suicide and no one would haveknown why.”

What she could not know was that the government shared her dim viewof Ranbaxy’s medicine. A criminal investigation of the company had beenunder way for a year and a half, prompted by employee allegations thatits manufacturing efforts were beset with fraud.

In August 2005, a Ranbaxy insider had passed whistle-blowinginformation to public-health experts in the United States. The papers(obtained by SELF) alleged that Ranbaxy altered testing data, concealedits deviation from safe manufacturing practices and used activepharmaceutical ingredients from unapproved sources. Its customers weretaking drugs that were potentially “subpotent, superpotent oradulterated,” according to a motion filed by the government in a U.S.District Court in Maryland last year.

The questionable drugs were being concocted in part for a programlaunched by George W. Bush called PEPFAR (President’s Emergency Plan forAIDS Relief), which sends medicine by the ton to Africa. Officialsworried that Ranbaxy had sold dubious AIDS drugs to the taxpayer-fundedprogram. And in the months that followed, evidence would surface thatsuspect Ranbaxy treatments were reaching Americans, too.

According to hundreds of pages of documents SELF obtained throughthe Freedom of Information Act, FDA inspectors would eventually findthat Ranbaxy delayed telling regulators for months about impurities inits version of the epilepsy drug gabapentin. The company also eitherfailed to report or reported late about complaints from patients takingfluoxetine, generic Accutane and sleeping pills. In an earlier case, thecompany had not told the FDA about a report from a pregnant woman whotook its sleeping pills and had a baby with a birth defect anddevelopmental delays. Ranbaxy admitted the errors and told the FDA theywould put procedures in place to prevent them from happening again.

The Ranbaxy scandal is the clearest evidence yet of the FDA’sstruggle to keep an eye on drug companies that increasingly make theirproducts in India and China. Brand-name drugs are made overseas, too,but globalization has been most dramatic in the generic industry. Atrecent inspection rates, it would take the FDA 13 years to see everyforeign plant once, whereas the agency inspects domestic factories every2.7 years, according to the U.S. Government Accountability Office.Inspectors generally spend less time on foreign inspections than they dodomestically and often must get clearance from foreign governments,which means that companies know they are coming.

Inspections commonly find unsterile work areas or substandardmanufacturing practices, former FDA officials say. Yet the agency oftenrelies on paperwork from the plants themselves to determine whetherproblems have been solved, says Bryan A. Liang, M.D., executive directorof the Institute of Health Law Studies at California Western School ofLaw in San Diego. In many cases, companies can give themselves a cleanbill of health. “The FDA does an inspection and rarely goes back,” Dr.Liang says. “Anything can happen beyond that point. It’s a hugeregulatory gap.”

Evidence of fraud

Many drugmakers do much more than make drugs: Through itssubsidiaries or outsourcing, Ranbaxy handles every stage of thegeneric-drug-development process, from supplying raw ingredients totesting drugs on volunteers. When a company has so much control over thepipeline, the FDA stands as one of the few checks on drug safety.

Those checks appear to have failed. The whistle-blower documentsprovided to SELF suggest the company either was dangerously sloppy oroutright fraudulent in an essential cornerstone of drug manufacturingknown as stability testing. Like a quart of milk in the fridge, drugscan only go bad. The question is how quickly their ingredients degrade;once they break down, the product becomes impure and potentially uselessor even hazardous. But Ranbaxy’s data showed the incredible: puritylevels that never decreased, that improved or that were identical forseparate batches, a statistical impossibility. SELF shared the 25 pagesof documents with a scientist who has overseen quality assurance for apharmaceutical manufacturing company; he concluded, “This is eitherfabricated data, or they don’t have people who can even do middle schoolchemistry.”

In one email exchange, a Ranbaxy manager in India notes that dataindicating no increase in impurities from 9 to 12 months “will certainlyraise doubts, we need to revise this number.” And an internal qualityreview shows that in several instances, the company mixedantiretroviral-drug ingredients for too long a time—which couldrender them ineffective or toxic. “If you’re a regulator and you look atthis, that’s when you say, ‘We’re padlocking your front door,'” says thescientist, adding, “If the FDA was in possession of this, it should beputting this medicine on the no-fly list.”

The agency had the documents—and was amassing more evidencethat the company’s products might be dangerous. In February 2006, a yearbefore Stephanie T. grappled with her relapse, the FDA sent inspectorsto one of Ranbaxy’s plants in India and found serious manufacturingproblems. In 2007, federal investigators raided Ranbaxy facilities inNew Jersey, seizing documents and computers. An inspection of a secondIndian factory in early 2008 found that medicine bound for the UnitedStates was improperly handled in a plant that makes penicillin, raisingthe specter of cross-contamination that could be lethal to people whoare allergic. And in its court filing last July, the government allegedthat Ranbaxy’s violations “continue to result in the introduction ofadulterated and misbranded products into interstate commerce.”

Yet the agency’s only regulatory response to these revelations wasto hold off approving applications for drugs manufactured in one of theIndian plants it had inspected. It did not pull the drugs from thatfactory off the market—or stop approving 39 applications for drugsmanufactured at the company’s other plants. “The FDA conductedpreapproval inspections for only 17 percent of the Ranbaxy applicationsapproved since 2005,” reveals Rep. John Dingell, Democrat of Michiganand sponsor of a bill to strengthen the FDA’s oversight of food and drugsafety. “It also allowed Ranbaxy to perform the key bioequivalencestudies in facilities owned by the firm and conducted by cliniciansemployed by the firm.”

A Ranbaxy spokesman, Charles Caprariello, says the company iscooperating fully with the FDA and the Justice Department and working toresolve authorities’ concerns swiftly. He notes that its New Jerseyfacility is not affected and continues to supply products for U.S.customers, with four new generics approved in 2009. “Ranbaxy remainscommitted to providing high quality medicines at affordable prices toU.S. patients,” he adds.

Last September, three years after learning of the whistle-blower’sallegations, the FDA finally issued an “import alert” for Ranbaxy drugs,effectively putting a hold on the importation of more than 30 drugs fromtwo of the company’s plants. A draft of the import alert had languishedat the agency, a source told SELF, sitting on the desk of an FDAdivision director before being sent back to a subordinate, where itspent more time.

The agency has now also imposed the rare and serious sanction ofscrutinizing all drug-safety data produced by one Indian plant becauseof its history of falsifications. “We’re being very vigorous,” saysJanet Woodcock, M.D., director of the FDA Center for Drug Evaluation andResearch, which oversees drug safety. Dr. Woodcock argues that theFDA’s recent actions against generic companies, including Ranbaxy, senda powerful signal that help promote “a culture of accountability aroundthe globe.”

Who can protect us?

The goal of low-cost medicine cannot come at the expense of safety.And as Dr. Kesselheim notes, in this bleak economy, generics have becomeeven more important, as the cost of drugs could lead patients to stoptaking needed medicine altogether. So how can authorities ensure genericdrugs are safe for patients?

For starters, says Dr. Gottlieb, the FDA’s Office of Generic Drugs,which controls approvals and inspections, needs more funding. “The FDAcan’t even keep pace with the inbox, let alone invest in betterscience,” he says. The need will become more acute in coming months, asgeneric companies push Congress for permission to make delicate,injectable biologic medicines such as Epogen and Neupogen, which areoften taken by cancer patients and are more complex to manufacture thantraditional pills are.

Doctors are eager to subject highly sensitive drugs that requiretime-release formulas or precise dosing to more extensive clinicaltesting, and Graedon would like to see random, off-the-shelf testing ofa generic’s ingredients and effectiveness after it hits the market. Moredynamic oversight would also require equal inspections of brand-name andgeneric plants, regardless of where they are in the world.

This is beginning to happen. In recent months, the FDA has openedbureaus in China, India, Central America and Europe and plans to expandits presence to Mexico, South America and the Middle East. Rep.Dingell’s bill, the FDA Globalization Act of 2009, would provide fundsfor further reforms. Still, cautions Dr. Woodcock, “there is no magicpoint in this process by which you can test everything. Let’s say wetest 10 tablets and they’re making 100,000? The manufacturer is incharge of the quality of the product, and our obligation is to make surethey meet their obligations.”

Dr. Stotland, of the American Psychiatric Association, says sheremains troubled that most state laws allow pharmacists to change atwill from brand names to generics (as well as among different generics).She argues that the law should require them to notify treatingphysicians of any change. As it stands, doctors who want to ensure theirbrand-name prescriptions are obeyed must write “Do not substitute” ontheir prescriptions—which does not guarantee that insurancecompanies will cover the extra cost. But Charles Mayr, a spokesman forthe Generic Pharmaceutical Association in Arlington, Virginia, arguesthat if pharmacists had the added burden of informing doctors, theywould be less likely to dispense generics. “It would help [brand-name]companies preserve monopolies,” he says, translating to higher pricesfor consumers.

In the meantime, patients can help themselves by knowing who made themedications they are taking and noting when their prescriptions changeand if they suffer new side effects or a relapse as a result. That’swhat Beth Hubbard has done. After her eight-month medical odyssey,Hubbard returned to the doctor who first prescribed Wellbutrin and whofailed to talk with her about whether her symptoms might be related to aswitch to a generic. She doesn’t blame him for what happened. Still, shesays, “doctors see too many people and they see them too fast, and theydon’t ask the difficult questions. You have to know your own body and beyour own advocate.”